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Pandemic flu clinical management of patients lim thorax 2007

1.
doi:10.1136/thx.2006.073080
2007;62;1-46Thorax
W S Lim
pandemic
with an influenza-like illness during an influenza
Pandemic flu: clinical management of patients
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2.
January 2007 Vol 62 Supplement I
Pandemic flu: clinical management of
patients with an influenza-like illness
during an influenza pandemic
Provisional guidelines from the British Infection
Society, British Thoracic Society and Health
Protection Agency in collaboration with the
Department of Health
AN INTERNATIONAL JOURNAL OF RESPIRATORY MEDICINE
thorax62_supp_I_cover.qxd 12/14/2006 6:05 PM Page 1
on 27 July 2009thorax.bmj.comDownloaded from

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N In those patients who are subsequently followed up in a
hospital outpatient clinic or by a general practitioner (GP), a
repeat chest x ray should be obtained at around six weeks if
respiratory symptoms or signs persist or where there is a
higher risk of underlying malignancy (especially smokers
and those over 50 years of age).
N Further investigations including a CT thoracic scan and
bronchoscopy should be considered if the chest x ray remains
abnormal at follow up.
S1.5 Microbiological investigations
S1.5.1 Early in a pandemic (UK alert levels 1, 2 and 3)
Virology—all patients
1. Nose and throat swabs in virus transport medium.
2. If presentation is more than seven days after onset of
illness, an ‘‘acute’’ serum (5–10 ml clotted blood) should be
collected and a ‘‘convalescent’’ sample (5–10 ml clotted
blood) obtained after an interval of not less than seven
days.
Bacteriology—patients with influenza-related
pneumonia
1. Blood culture (preferably before antibiotic treatment is
commenced)
2. Pneumococcal urine antigen (20 ml urine sample)
3. Legionella urine antigen (20 ml urine sample)
4. Sputum gram stain, culture and antimicrobial suscept-
ibility tests on samples obtained from patients who:
(i) are able to expectorate purulent samples, and
(ii) have not received prior antibiotic treatment.
5. Paired serological examination for influenza/other agents.
Acute serum should be collected and a ‘‘convalescent’’
sample obtained after an interval not less than seven days
(both 5–10 ml clotted blood).
S1.5.2 Once a pandemic is established (UK alert level 4)
Virology—not routinely recommended
Bacteriology—patients with influenza-related
pneumonia in accordance to the severity of illness
(a) Non-severe pneumonia (CURB-65 Score 0, 1 or 2)
– No routine testing.
– In patients who do not respond to empirical antibiotic
therapy, sputum samples should be sent for Gram stain
culture and antimicrobial susceptibility tests.
(b) Severe pneumonia (CURB-65 Score 3, 4 or 5, or bilateral
chest x ray changes)
– Blood culture, preferably before antibiotic treatment is
commenced
– Pneumococcal urine antigen (20 ml urine)
– Sputum gram stain, culture and antimicrobial
susceptibility tests on samples obtained from patients
who are able to expectorate purulent samples, and have
not received prior antibiotic treatment.
– Paired serological examination for influenza/other
agents. ‘‘Acute’’ serum should be collected and a
‘‘convalescent’’ sample obtained after an interval not less
than seven days (both 5–10 ml clotted blood).
– Tracheal or endotracheal aspirate samples, if avail-
able, should be sent for Gram stain, culture and
antimicrobial susceptibility testing.
S1.6 General management
S1.6.1 Initial management
N Hypoxic patients should receive appropriate oxygen therapy
with monitoring of oxygen saturations and inspired oxygen
concentration with the aim to maintain PaO2 >8 Kpa and
SaO2 >92%. High concentrations of oxygen can safely be
given in uncomplicated pneumonia.
N Oxygen therapy in patients with pre-existing COPD compli-
cated by ventilatory failure should be guided by repeated
arterial blood gas measurements. Non-invasive ventilation
(NIV) may be helpful.
N In patients without pre-existing COPD who develop respira-
tory failure, NIV may be of value as a bridge to invasive
ventilation in specific circumstances when level 3 beds are in
high demand. Respiratory and/or critical care units experi-
enced in the use of NIV are best placed to ensure the
appropriate infection control measures are adopted at all
times.
N Patients should be assessed for cardiac complications and
also volume depletion and their need for additional
intravenous fluids.
N Nutritional support should be given in severe or prolonged
illness.
S1.6.2 Monitoring in hospital
N Temperature, respiratory rate, pulse, blood pressure, mental
status, oxygen saturation and inspired oxygen concentration
should be monitored and recorded initially at least twice
daily and more frequently in those with severe illness or
requiring regular oxygen therapy. An Early Warning Score
system is a convenient way to perform this.
N In patients who are not progressing satisfactorily a full
clinical reassessment and a repeat chest radiograph are
recommended.
S1.6.3 Discharge and follow up
N Patients should be reviewed 24 hours prior to discharge.
Those with two or more of the following unstable clinical
factors should be considered for remaining in hospital:
(1) temperature .37.8˚C
(2) heart rate .100/min
(3) respiratory rate .24/min
(4) systolic blood pressure ,90 mmHg
(5) oxygen saturation ,90%
Table A General investigations
Test Who this applies to
Full blood count All patients
Urea and electrolytes All patients
Liver function tests All patients
Chest x ray All patients
Pulse oximetry All patients. If ,92% on air, then arterial
blood gases
Electrocardiogram Patients with cardiac and respiratory
complications or comorbid illnesses
C-reactive protein If influenza-related pneumonia is suspected
i2 Provisional guidelines from the BIS/BTS/HPA with the Department of Health
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7.
(6) inability to maintain oral intake
(7) abnormal mental status.
N Follow up clinical review should be considered for all
patients who suffered significant complications or who had
significant worsening of their underlying disease, either with
their GP or in a hospital clinic.
N At discharge or at follow up, patients should be offered
access to information about their illness, take home
medication and any follow up arrangements.
N It is the responsibility of the hospital team to arrange the
follow up plan with the patient and the GP.
S1.7 Use of antivirals
N Individuals should only be considered for treatment with
antivirals (neuraminidase inhibitors) if they have all of the
following:
(1) an acute influenza-like illness (ILI)
(2) fever (.38˚C) and
(3) been symptomatic for two days or less.
N Treatment schedule: adults, oseltamivir 75 mg every
12 hours for five days (dose to be reduced by 50% if
creatinine clearance is less than 30 ml/min—that is, 75 mg
od)
N Patients who are unable to mount an adequate febrile
response—for example, the immunocompromised or very
elderly—may still be eligible for antiviral treatment despite
lack of documented fever.
N Hospitalised patients who are severely ill, particularly if also
immunocompromised, may benefit from antiviral treatment
started more than 48 hours from disease onset, although
there is no evidence to demonstrate benefit, or lack of, in
such circumstances.
S1.8 Antibiotic management
S1.8.1 Influenza not complicated by influenza-related
pneumonia
N Previously well adults with acute bronchitis complicating
influenza, in the absence of pneumonia, do not routinely
require antibiotics.
N Antibiotics should be considered in those previously well
adults who develop worsening symptoms (recrudescent
fever or increasing dyspnoea).
N Patients at high risk of complications or secondary infection
(Appendix 2) should be considered for antibiotics in the
presence of lower respiratory features.
N Most patients can be adequately treated with oral antibiotics.
N The preferred choice includes co-amoxiclav or a tetracycline.
N A macrolide such as clarithromycin (or erythromycin) or
a fluoroquinolone active against Streptococcus pneumoniae
(S pneumoniae) and Staphylococcus aureus (S aureus) is an
alternative choice in certain circumstances.
S1.8.2 Non-severe influenza-related pneumonia
N Most patients can be adequately treated with oral antibiotics.
N Oral therapy with co-amoxiclav or a tetracycline is preferred.
N When oral therapy is contraindicated, recommended par-
enteral choices include intravenous co-amoxiclav, or a
second or third generation cephalosporin (cefuroxime or
cefotaxime).
N A macrolide (erythromycin or clarithromycin) or a fluor-
oquinolone active against S pneumoniae and S aureus is an
alternative regimen where required—for example, for those
intolerant of penicillins. Currently levofloxacin and moxi-
floxacin are the only recommended fluoroquinolones
licensed in the UK.
N Antibiotics should be administered within four hours of
admission.
S1.8.3 Severe influenza-related pneumonia
N Patients with severe pneumonia should be treated immedi-
ately after diagnosis with parenteral antibiotics.
N An intravenous combination of a broad spectrum beta-
lactamase stable antibiotic such as co-amoxiclav or a second
(for example, cefuroxime) or third (for example, cefotaxime)
generation cephalosporin together with a macrolide (for
example, clarithromycin or erythromycin) is preferred.
N An alternative regimen includes a fluoroquinolone with
enhanced activity against pneumococci together with a
broad spectrum b-lactamase stable antibiotic or a macrolide.
Currently levofloxacin is the only fluoroquinolone with an
intravenous formulation licensed in the UK.
S1.8.4 Route and duration of antibiotic
N Patients treated initially with parenteral antibiotics should
be transferred to an oral regimen as soon as clinical
improvement occurs and the temperature has been normal
for 24 hours, providing there is no contraindication to the
oral route.
N For most patients admitted to hospital with non-severe and
uncomplicated pneumonia, seven days of appropriate anti-
biotics is recommended.
N For those with severe, microbiologically undefined pneumo-
nia, 10 days’ treatment is proposed. This should be extended
to 14–21 days where S aureus or Gram negative enteric bacilli
pneumonia is suspected or confirmed.
S1.8.5 Failure of empirical antibiotics
N For those with non-severe pneumonia in hospital on
combination therapy, changing to a fluoroquinolone with
effective pneumococcal and staphylococcal cover is an
option.
N Adding further antibiotics effective against MRSA is an
option for those with severe pneumonia not responding to
combination antibiotic therapy.
SYNOPSIS 2 CLINICAL MANAGEMENT OF CHILDREN
REFERRED TO HOSPITAL
S2.1 Severity assessment in children (see Appendix 5)
S2.1.1 In the community
N Coughs and mild fevers. These children should be treated
at home by parents with antipyretics and fluids (note:
aspirin should not be used in children).
N High fever (.38.5˚C) and cough or influenza-like
symptoms. These children should seek advice from a
community health professional. If there are no features that
put them at high risk of complications they should be
treated with oseltamivir, and given advice on antipyretics
and fluids. Children aged ,1 year and those at risk of
complications (Appendix 2) should be seen by a genral
practitioner.
N High fever (.38.5˚C) and cough or influenza-like
symptoms, plus at risk group. These children should be
seen by a GP or in A&E. Children may be considered at
increased risk of complications if they have cough and fever
(or ILI) and temperature .38.5˚C, plus either chronic
comorbid disease or one of following features:
Pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic i3
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8.
– breathing difficulties
– severe earache
– vomiting .24 hours
– drowsiness.
These patients should be offered an antibiotic as well as
oseltamivir (in those .1 year of age) and advice on antipyretics
and fluids. Children aged ,1 year with none of the above
features should be treated with antipyretics and fluids with a
low threshold for antibiotics if they become more unwell.
S2.1.2 Hospital admission
Indicators for hospital admission are:
(1) Signs of respiratory distress
– markedly raised respiratory rate
– grunting
– intercostal recession
– breathlessness with chest signs
(2) Cyanosis
(3) Severe dehydration
(4) Altered conscious level
(5) Complicated or prolonged seizure
(6) Signs of septicaemia—extreme pallor, hypotension, floppy
infant
Most children admitted to hospital are likely to need oxygen
therapy and/or intravenous support as well as antibiotics and
oseltamivir.
Indications for transfer to high dependency or intensive care
are:
(1) failure to maintain a SaO2 of .92% in FiO2 of .60%
(2) the child is shocked
(3) severe respiratory distress and a raised PaCO2 (.6.5 Kpa)
(4) rising respiratory rate and pulse rate with clinical evidence
of severe respiratory distress with or without a raised
PaCO2
(5) recurrent apnoea or slow irregular breathing
(6) evidence of encephalopathy
When there are no paediatric intensive care unit beds
available, children will have to be triaged on the basis of the
severity of their acute and coexisting disease, and the likelihood
of their achieving full recovery.
S2.2 General investigations for children in hospital
N A full blood count with differential, urea, creatinine and
electrolytes, liver enzymes and a blood culture should be
done in all severely ill children.
N A chest x ray should be performed in children who are
hypoxic, have severe illness or who are deteriorating despite
treatment.
N Pulse oximetry should be performed in every child being
assessed for admission to hospital with pneumonia.
S2.3 Microbiological investigations in hospital
S2.3.1 Early in a pandemic (UK alert levels 1, 2 and 3)
Virology—all children
(1) Nasopharyngeal aspirate or nose and throat swabs.
(2) If presentation is more than 7 days after onset of illness, an
‘‘acute’’ serum (2–5 ml clotted blood) should be collected
and a ‘‘convalescent’’ sample (2–5 ml clotted blood)
obtained after an interval of not less than 7 days.
Bacteriology—children with influenza-related
pneumonia
(1) Blood culture (before antibiotic treatment is commenced).
(2) Sputum samples obtained from older children.
(3) Paired serological examination for influenza/other agents.
S2.3.2 Once a pandemic is established (UK alert level 4)
Virology—not routinely recommended
Bacteriology—children with influenza-related pneumonia
(1) Blood culture (before antibiotic treatment is commenced).
(2) Sputum samples obtained from older children.
(3) Paired serological examination for influenza/other agents.
S2.4 General management of children admitted to
hospital
N Patients whose oxygen saturation is 92% or less while
breathing air should be treated with oxygen given by nasal
cannulae, head box, or face mask to maintain oxygen
saturation above 92%.
N When children are unable to maintain oral intake, supple-
mentary fluids should, when possible, be given by the
enteral route. Intravenous fluids in those with severe
pneumonia should be given at 80% basal levels.
N Children can be safely discharged from hospital when they
(1) are clearly improving
(2) are physiologically stable
(3) can tolerate oral feeds
(4) have a respiratory rate ,40/min (,50/min in infants)
(5) have an awake oxygen saturation of .92% in air.
S2.5 Antiviral therapy in children
N In the setting of a pandemic, children should only be
considered for treatment with antivirals if they have all of
the following:
(1) an acute ILI
(2) fever (.38.5˚C) and
(3) been symptomatic for two days or less.
N Oseltamivir is the antiviral agent of choice.
N In children who are severely ill in hospital oseltamivir may
be used if the child has been symptomatic for ,6 days (but
there is no evidence to demonstrate benefit or lack of it in
such circumstances).
S2.6 Antibiotic therapy in children
N Children (a) who are at risk of complications of influenza or
(b) with disease severe enough to merit hospital admission
during an influenza pandemic should be treated with an
antibiotic that will provide cover against S pneumoniae,
S aureus and Haemophilus influenzae (H influenzae).
N For children under 12 years co-amoxiclav is the drug of
choice. Clarithromycin or cefuroxime should be used in
children allergic to penicillin. For children over 12 years
doxycycline is an alternative.
N Oral antibiotics should be given if oral fluids are tolerated.
i4 Provisional guidelines from the BIS/BTS/HPA with the Department of Health
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9.
N Children who are severely ill with pneumonia complicating
influenza should have a second agent added to the regime
(for example, clarithromycin or cefuroxime) and the drugs
should be given intravenously to ensure high serum and
tissue antibiotic levels.
1 INTRODUCTION
1.1 Scope and purpose
This document contains guidance for health professionals
regarding the treatment of pandemic influenza, agreed by
experts from the British Infection Society, the British Thoracic
Society and the Health Protection Agency. It is published as
official UK guidance by the Department of Health in England
and covers treatment in hospitals and the community, of both
adults and children. It is intended for use in the UK in the event
that the World Health Organization declares that an influenza
pandemic has started,1
and the Department of Health in
England (UK-wide lead agency on pandemic influenza,
including the devolved administrations) has declared UK
Pandemic Alert Level 2 (cases of pandemic influenza identified
within the UK; see Appendix 1).2
This guidance should be read in conjunction with UK
Infection Control Guidance for Pandemic Influenza,3
the
Department of Health UK Pandemic Influenza Contingency
Plan,2
Operational Guidance for Health Service Planners,4
and
the Operational Framework for stockpiling, distributing and
using antiviral drugs in the event of pandemic influenza5
and
the Primary Care Operational Plan.
To facilitate preparedness planning, this document has been
written in advance of the emergence of the next influenza
pandemic, at a time when the identity of the causative virus
remains unknown.
These guidelines are based on the best evidence available
from previous pandemic and interpandemic influenza periods.
The guidance may evolve as clinicopathological information on
the eventual pandemic virus emerges. Once an influenza
pandemic is under way, users are strongly urged to refer to
the most up-to-date version of these guidelines (from web-
based access points).
1.2 Context
Seasonal influenza is a familiar infection in the UK, especially
during winter. Every year strains of influenza (type A or B)
circulate, giving rise to clinical consultations in primary care
(age-specific impact varies by season), episodes of hospital
treatment (mainly in older persons and young children, but
occasionally in working age adults), and deaths (mainly in the
elderly). Treatment in primary care and hospital may be
required due to the direct effects of influenza virus infection
or its possible complications, most commonly secondary
bacterial pneumonia. Increases in GP consultations for ILI
and winter bed pressures are frequently associated with periods
of known community influenza activity.6
Pandemic influenza occurs when a new influenza A virus
subtype emerges which is markedly different from recently
circulating subtypes and strains, and is able to:
N infect humans;
N spread efficiently from person to person;
N cause significant clinical illness in a high proportion of those
infected.
Because the virus is novel in humans, a high proportion of
the population will have little or no immunity, producing a
large pool of susceptible persons; accordingly the disease
spreads widely and rapidly.
Influenza pandemics occur sporadically and unpredictably.
In 1918, a devastating and unusual pandemic caused by
influenza A/H1N1 (‘‘Spanish flu’’) killed between 20 and 40
million people worldwide. Other pandemics that followed had a
less devastating impact but were nevertheless severe. Influenza
A/H2N2 (‘‘Asian flu’’) emerged in 1957 and H3N2 (‘‘Hong Kong
flu’’) in 1968; both caused roughly 1 million excess deaths
worldwide.7
The circumstances still exist for a new influenza virus with
pandemic potential to emerge and spread, and the longest
interval so far recorded between pandemics is 39 years
(1918–57). The unpredictability of the timing of the next
pandemic is underlined by the occurrence of several large
outbreaks of highly pathogenic avian influenza associated
with epizootic transmission to humans.8
By far the most
serious has been the massive and unprecedented outbreak of
highly pathogenic influenza (A/H5N1) affecting poultry in
East and South East Asia in late 2003, which is still
continuing. This outbreak has so far been associated with a
small number of human cases but a high proportion of
deaths. Recently, epidemiological and virological changes
have been reported from northern Viet Nam which may
indicate that the virus is beginning to adapt to humans.9
Although the emergence of an A/H5N1 strain with capacity to
spread efficiently between humans is neither inevitable nor
imminent, international concern has increased regarding the
possibility that avian influenza A/H5N1 may evolve to
produce the next pandemic.
Other events and developments that inform the creation of
this guidance are the development and licensing of a new class
of drug (neuraminidase inhibitors) active against influenza,
and UK government’s announcement of plans to procure 14.6
million treatment courses of oseltamivir (TamifluH)10
for use in
the UK in the event of a pandemic.
1.3 Who are these guidelines aimed at?
These guidelines are offered for the guidance of all UK hospital
doctors and primary care physicians. In the event of a
pandemic, it is envisaged that all healthcare practitioners,
regardless of individual specialisation, may be involved in the
management of patients with influenza. It is intended that
these guidelines also be of value to healthcare practitioners who
do not usually manage patients with influenza but may be
called upon to do so in a pandemic situation. Modification of
some recommendations at a local level may be necessary in
specific instances.
These guidelines are not relevant for the management of
patients affected by seasonal influenza, sporadic acute exacer-
bations of COPD, lower respiratory tract infections or commu-
nity acquired pneumonia (CAP).
1.4 Primary care
At the primary care level, a national Operational Plan including
the following three broad areas is deemed important:
(1) clinical management of patients with influenza
(2) management of patient demand, including patients who do
not have influenza
(3) health service delivery plans.
These guidelines cover the first of these areas and will serve
as the source document for the Primary Care Operational
Plan. The Primary Care Operational Plan will incorporate all
three areas within a single reference and is being developed by
the Department of Health in collaboration with the Royal
College of General Practitioners and the British Medical
Association.
Pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic i5
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10.
1.5 Healthcare delivery modes
Even though it is impossible to predict with certainty the
impact of the next pandemic, based upon the available
epidemiological and modelling information, it is clear that it
will generate demands for health care which may saturate or
overwhelm normal NHS acute services for a period of time,
perhaps several weeks or months. Accordingly, it should be
anticipated that the NHS (in common with all health systems
around the world) will need to revert to emergency arrange-
ments. These are laid out in further detail in Operational
Guidance for Health Service Planners,4
the UK Operational
Framework for stockpiling, distributing and using antiviral
drugs in the event of pandemic influenza5
and in the Primary
Care Operational Plan. With regard to the delivery of medical
care for patients with influenza this is normally achieved
through:
N GP treatment of community patients ‘‘well’’ enough to be
managed in the community
N hospital care in acute medicine for persons considered too ill
to be managed at home.
In the event of a pandemic, the following additional care
settings may have to be considered as the threshold for hospital
admission rises:
N treatment of patients in the community (who would
normally receive care from a GP) by other healthcare
professionals (nurses, paramedics, pharmacists, etc) follow-
ing treatment guidance laid out in this publication and using
prescription-only medicines according to Patient Group
Directives
N treatment of patients in their own homes or in temporary
intermediate care facilities by a GP, following treatment
guidance laid out in this publication when, under normal
circumstances, such patients would have been admitted for
hospital care
N treatment of severely ill patients in hospital by medical and
nursing teams who do not normally manage patients with
influenza or CAP, in areas of the hospital not normally used
for providing medical care (for example, surgical teams and
bed space diverted from routine elective work towards
pandemic response).
1.6 Grading of recommendations
The recommendations offered in the current guidelines are
based on a matrix of evidence centred mainly around seasonal
influenza, expert opinion and group consensus. Grading of
these recommendations based on the strength of the evidence
base was deemed inappropriate.
2 EPIDEMIOLOGY AND HEALTH IMPACT
PROJECTIONS
Summary
1. The scale and severity of illness (and hence consequences)
caused by pandemic influenza generally exceed those of
even the most severe winter epidemics.
2. Mortality in the UK is likely to exceed 50,000 deaths,
possibly much higher.
3. Besides the elderly, excess mortality is also likely in
younger adults and children.
4. Modelling studies suggest that after a case occurs in Hong
Kong, because of international travel, it will take less than
one month for the virus to reach the UK.
5. Once cases begin to occur in the UK it will take only 2–3
weeks before activity is widespread and roughly a further
three weeks (six weeks after initial cases in UK) until
activity peaks.
6. It is possible that there will be more than one epidemic
wave (with an interval of several months) and, if a second
wave occurs, it may be more severe than the first.
7. Cumulative clinical and serological attack rates across all
waves together may be in the order of 25% and 50%
respectively.
8. Increases in demand for healthcare services are likely to be
very substantial in both primary care and hospital settings.
2.1 Introduction
When an influenza pandemic occurs, a substantial proportion
(possibly all) of the population is likely to be non-immune,
producing a large pool of susceptible persons. In past
pandemics, the scale and severity of illness (and hence
consequences) have been variable but broadly of a higher order
than even the most severe winter epidemics. It is reasonable to
expect this to be the case with the next pandemic as well.
2.2 Excess mortality
Excess mortality due to influenza occurs in most winter seasons
but is especially marked during epidemics. The average annual
excess mortality attributable to influenza in recent years is
around 12,000 deaths per annum in England and Wales,11
although there is considerable yearly variation and some years
are notably much higher than the average (estimated 26,000 in
1989/90 epidemic). Excess mortality in England and Wales
associated with the three pandemics of the twentieth century
has also varied widely; this was estimated at 198,000 civilians
in 1918/19, and 37,500 in 1957/58. In 1968/69 and 1969/70
(both seasons considered to be associated with the influenza A/
H3N2 pandemic), there were an estimated 31,000 and 47,000
deaths respectively.7
Therefore the extent of mortality asso-
ciated with the next pandemic cannot be reliably predicted
although it is reasonable to plan for a scenario worse than a
severe winter epidemic of normal influenza.
2.3 Age distribution of morbidity and mortality
Typically, there are changes in the age distribution of cases
compared with seasonal influenza. Mortality, which in typical
seasonal influenza is usually confined to age groups over 65
years, tends to be increased in younger age groups. The size of
any increase in morbidity and mortality and the extent to
which a shift in age distribution occurs depend on a variety of
factors including the nature of the pandemic virus and pre-
existing immunity but appears to be a consistent phenom-
enon.12
Therefore, clinicians can expect to see relatively larger
amounts of influenza-related illness in younger adults com-
pared with normal winter activity. At least one third of all
excess deaths may be expected in persons under 65 years of age.
2.4 Geographical and temporal spread
Virological and clinical surveillance of influenza have improved
markedly since the last pandemic in 1968. However, the extent
of international travel has also grown. Modelling studies using
transmission characteristics based on the 1968/69 pandemic
and international air-traffic data from 2002 indicate that the
approximate delay between a first case in Hong Kong and first
introduction to UK will be less than one month13
In terms of the
spread within the UK, it will probably take only 2–3 weeks from
the initial introduction(s) until activity is widespread and a
further three weeks (six weeks from initial UK cases) until
activity peaks.
The temporal and spatial spread of a pandemic strain is
important, particularly in terms of the demand placed on
healthcare services. Pandemic activity taking the form of a brief
i6 Provisional guidelines from the BIS/BTS/HPA with the Department of Health
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11.
but severe peak in cases will be more difficult for all services to
cope with, compared with an identical number of cases distributed
over a longer time course. For example, during the A/H3N2
pandemic a long first wave occurred in the winter of 1968/69 with
morbidity and mortality approximately at the same level as the
previous seasonal influenza; but in the following winter of 1969/
70 a short and more severe epidemic occurred with a threefold
higher peak in general practice consultation rates and a fourfold
higher peak in mortality attributed to influenza, bronchitis and
pneumonia. The high peak in consultation rates is well illustrated
in figure 2.1.
2.5 Pandemic waves
In 1918/19, the A/H1N1 pandemic occurred in three distinct
epidemic waves: early spring 1918, autumn 1918 and late
winter 1919. The second wave was by far the largest and case-
fatality rates were also higher than in the first wave. The A/
H3N2 pandemic caused an epidemic wave in the winter of
1968/69 but a more severe one in 1969/70. In contrast, the
second wave of the 1957/58 pandemic in the UK was very small
in comparison to the first.7
Thus it should be considered a
possibility that more than one wave of influenza will occur
within a few months of the emergence of a pandemic virus and
a subsequent wave could be worse than the first.
2.6 Health impact projections
It is impossible to predict reliably with precision the level of
excess mortality that will be experienced in the next pandemic.
However, table 2.1 illustrates the broad range of excess
mortality that it is reasonable to consider, based on various
realistic combinations of case fatality rate and clinical attack
rates derived from previous pandemics and epidemics.
A case fatality rate of 0.37% corresponds to the aggregate rate
observed in recent epidemic seasons (1989/90, 1991/92, 1993/
94, 1995/96, 1996/97, 1997/98 and 1998/99) and the 1957
pandemic, although the overall case-fatality rate observed in
the 1918–19 pandemic was in the region of 1–2%. A clinical
attack rate of around 25% corresponds to the approximate
clinical attack rate seen in all three previous pandemics of the
twentieth century. Thus, a figure of at least 50,000 excess
deaths is likely.
Using mathematical projections, it is possible to illustrate the
potential impact of the next pandemic, but these do not
amount to accurate predictions. Table 2.2 summarises the
number of events that might be expected by a GP with 1000
patients on his/her list and by a Primary Care Trust (PCT)
serving a population of 100,000 persons.
Using the same assumptions, table 2.3 illustrates the number
of events by week over an assumed 15 week (single wave)
pandemic period in a typical PCT population of 100 000. Most
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1966/67
1967/68
1968/69
1969/70
1970/71
1971/72
1972/73
1973/74
1974/75
1975/76
1976/77
1977/78
1978/79
1979/80
1980/81
1981/82
1982/83
1983/84
1984/85
1985/86
1986/87
1987/88
1988/89
1989/90
1990/91
1991/92
1992/93
1993/94
1994/95
1995/96
1996/97
1997/98
1998/99
1999/00
2000/01
2001/02
2002/03
2003/04
2004/05
Year
Rateper100000population
1969/70
1972/73
1975/76
1989/90
1967/68
Figure 2.1 Royal College of General Practitioners’ index for influenza and influenza-like illness, 1966 and 2005 (year marked at start of season, that is,
week 40 (October)).
Table 2.1 (A) Range of possible excess deaths based on
various permutations of case-fatality rates and clinical attack
rates for England and Wales
Overall case
fatality rate
Clinical attack rate
10% 25% 50%
0.37% 19,300 48,400* 96,700
1.00% 51,700 129,200 258,400
1.5% 77,100 192,700 385,400
2.5% 129,200 323,000 645,900
*Corresponds to aggregate for recent epidemics (see text).
Table 2.1 (B) Range of possible excess deaths based on
various permutations of case-fatality rates and clinical attack
rates for the UK
Overall case
fatality rate
Clinical attack rate
10% 25% 50%
0.37% 21,500 53,700* 107,500
1.00% 56,700 141,800 283,700
1.5% 85,100 212,800 425,500
2.5% 141,800 354,600 709,300
*Corresponds to aggregate for recent epidemics (see text).
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circulating in the community.15 17 20
In cohort studies, correla-
tion of ILI with laboratory-confirmed influenza infection ranges
from 25–45%, while in clinical trials rates of 70% have been
consistently reported.15 21–23
These findings relate to influenza infections during inter-
pandemic periods. During a global influenza pandemic, when a
pandemic strain is known to be circulating locally in an
immunologically susceptible population, the presence of an ILI
would be expected to be highly predictive for influenza
infection. (However, the extent to which a clinical diagnosis
of ILI becomes predictive during a pandemic will also be
determined by the behaviour of the public. If many, who would
not normally present to a health professional, are prompted to
present, then the predictive value of a clinical diagnosis of ILI
will be reduced.)
3.2 What are the clinical features of uncomplicated
influenza?
The following description will relate mainly to interpandemic
influenza A infections. Influenza B and C are not considered
pandemic threats. Different strains may be associated with
different clinical presentations and disease severity. For instance,
there is evidence to suggest that the H3N2 subtype causes more
severe disease than H1N1 subtype.24
The spectrum of clinical
disease associated with a new influenza A subtype (for example,
a pandemic strain) cannot be determined currently and may
differ from that described for interpandemic influenza.
The incubation period prior to the onset of symptoms is
commonly 2–4 days (range 1–7 days). In adults, the illness
typically presents as an abrupt onset of fever accompanied by a
range of other symptoms as listed in Box 3.2.25–29
Fever is the paramount symptom and may reach 41˚C although
more usually it ranges between 38–40˚C. The peak occurs within
24 hours of onset and lasts typically for three days (range 1–5
days).25–29
The cough is generally dry although in up to 40% of
cases it may be productive. A productive cough together with chest
tightness and substernal soreness is more common in patients
with underlying chronic lung disease. Myalgia affects mainly the
back and limbs. Gastrointestinal symptoms such as vomiting and
diarrhoea are uncommon (,10%) in adults. Abdominal pain is
rare.
Clinical findings include a toxic appearance in the initial
stages, hot and moist skin, a flushed face, injected eyes and
hyperaemic mucous membranes around the nose and pharynx.
Tender cervical lymphadenopathy is found in a minority
(,10%) of cases. Wheezing or lung crackles are recognised
findings (,10%) more commonly noted in patients with
coexisting chronic lung disease.
Although the overall clinical picture of uncomplicated
influenza in any specific age group is similar for different
influenza A subtypes, the frequency of certain symptoms may
vary. For instance, during the ‘‘Asian’’ pandemic of 1957
(H2N2), headache and sore throat were frequent initial
symptoms.30
In uncomplicated infection, the illness usually resolves in
seven days although cough, malaise and lassitude may persist
for weeks.
Box 3.1 Clinical case definition of influenza
(March 2006)
The presence of fever and new (or, in those with chronic lung
disease, worsening) cough of acute onset in the context of
influenza circulating in the community. (Important note: this
definition may be modified once a pandemic occurs.)
Box 3.2 Range of symptoms associated with
uncomplicated influenza infection
N Cough (,85%)
N Malaise (,80%)
N Chills (,70%)
N Headache (,65%)
N Anorexia (,60%)
N Coryzal symptoms (,60%)
N Myalgia (,53%) and
N Sore throat (,50%).
Table 3.1 Complications associated with influenza infection in adults
Complication Incidence Comments
Respiratory
Acute bronchitis Common More common in elderly and those with chronic medical
conditions
Primary viral pneumonia Uncommon Onset within 48 hours of start of fever
Secondary bacterial pneumonia Common Typically occurs four to five days after onset of illness
Cardiovascular
ECG abnormalities Common Non-specific T wave and rhythm changes, ST segment
deviation. Mostly not associated with cardiac symptoms
Myocarditis Rare
Pericarditis Rare
Muscle
Myositis Uncommon Occurs during early convalescence
Myoglobinuria and renal failure Rare
Central nervous system
Encephalitis/encephalopathy Rare Occurs within first week of illness. More common in
children and in Japan
Transverse myelitis Very rare
Guillain-Barre´ syndrome Very rare
Others
Otitis media Common Much more common in children
Toxic shock syndrome Rare
Parotitis Very rare
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3.3 What complications are associated with influenza
infection?
Influenza virus infection has been associated with worsening in
the clinical condition of patients with a range of existing
medical conditions, such as heart failure, diabetes, coronary
heart disease, asthma and COPD.
In addition, specific complications associated with influenza
infection regardless of coexisting medical conditions are
recognised (table 3.1). Based on data from interpandemic
influenza, certain persons are identified as being at high risk
from influenza-related complications. Such patients are similar
to the group currently recommended for influenza vaccination
by the Department of Health. These include those of all ages
with chronic respiratory disease including asthma, chronic
heart disease, chronic renal disease, chronic liver disease,
immunosuppression due to disease or treatment, or diabetes
mellitus, and all those aged 65 years or older, or those in long
stay residential care (see Appendix 2).
In the course of a pandemic, it may emerge that the patient
group at high risk of complications differs from the group
currently identified. In such circumstance, details of the ‘‘high
risk’’ patient group will be altered according to relevant clinico-
epidemiological data.
3.3.1 Influenza-related pneumonia
The incidence of pneumonia (defined as a combination of
respiratory symptoms and signs supported by chest radio-
graphic changes consistent with infection) complicating influ-
enza infection varies widely, from 2% to 38%, and is dependent
on viral and host factors.25–27
Pneumonia generally occurs more
frequently and with greater severity in patients with pre-
existing chronic cardiac and respiratory conditions.
Patients who develop pneumonia may present with symp-
toms and signs indistinguishable from pneumonia related to
other viral and bacterial pathogens. In the context of an
influenza pandemic, the presence of an ILI and new or
worsening dyspnoea should prompt a careful examination for
the presence of complicating pneumonia. Two main types of
influenza-related pneumonia are recognised: primary viral
pneumonia and secondary bacterial pneumonia.25–28
Primary viral pneumonia
Patients with primary viral pneumonia typically become
breathless within the first 48 hours of onset of fever. An
initially dry cough may become productive of blood-stained
sputum. Cyanosis, tachypnoea, bilateral crepitations and
wheeze on chest examination and leucocytosis are usual. The
commonest chest radiographic abnormality is of bilateral
interstitial infiltrates predominantly in the mid-zones, although
focal consolidation is also well recognised. Rapid clinical
deterioration with respiratory failure may ensue.31
The mortal-
ity in hospitalised patients is high (.40%) despite maximum
supportive treatment on intensive care.25–28
In the majority of
fatal cases, death occurs within seven days of hospital
admission.
Secondary bacterial pneumonia
Secondary bacterial pneumonia is more common (up to four
times) than primary viral pneumonia. Typically, symptoms and
signs of pneumonia develop during the early convalescent
period (4–5 days from onset of initial symptoms). In others,
symptoms of pneumonia blend in with the initial symptoms of
influenza. Chest radiography usually demonstrates a lobar
pattern of consolidation. Mortality rate ranges from 7% to
24%,25–29 32
although some small studies report higher mortality
rates.
The spectrum of pathogens implicated is similar to that
observed in CAP and includes S pneumoniae, S aureus, H influenzae
and Groups A, C and G beta-haemolytic streptococci.27 28 33–35
Different pathogens have predominated at different times. For
instance, in the 1918 pandemic, H influenzae, beta-haemolytic
streptococci and S pneumoniae were the predominant pathogens
isolated. In 1968, S pneumoniae was the predominant pathogen
(48%) followed by S aureus (26%) and non-typeable H influenzae
(11%).34
Notably, S aureus was identified two and a half times
more frequently during the 1968 pandemic compared to
pneumonia occurring in the interpandemic period.34 36
Secondary staphylococcal pneumonia is associated with a
higher incidence of lung abscess formation (14% v 2%) and
carries a poorer prognosis compared to non-staphylococcal
pneumonias (mortality 47% v 16%).25 29 32 37
During the 1957
pandemic, S aureus was the predominant bacterial pathogen
isolated in fatal cases of influenza-related pneumonia (up to
69% of cases in some series).25
Mixed viral-bacterial pneumonia
Bacterial and viral pneumonia can occur concurrently. In these
instances, the chest radiograph may demonstrate lobar
consolidation superimposed on bilateral diffuse lung infiltrates.
The mortality rate in mixed viral-bacterial pneumonia is high
(.40%), as for primary viral pneumonia.25–28
3.3.2 Cardiovascular
Minor abnormalities on ECG such as ST segment deviation, T
wave changes and rhythm disturbances have been described in
uncomplicated influenza illness. They have been reported in up
to 81% of patients hospitalised with influenza.25
Most do not
have cardiac symptoms. Myocarditis and pericarditis are
occasionally encountered in severe illness.38 39
Postmortem
evidence of necrotising myocarditis has been reported in
patients without clinically significant myocarditis in the
antemortem period.
3.3.3 Myositis
In contrast with myalgia affecting the back and limbs, which is
common on initial presentation, myositis generally develops
after the subsidence of the acute upper respiratory tract
symptoms. The gastrocnemius and soleus muscles are typically
involved with pain and tenderness to palpation. Complete
recovery usually occurs in three days. Elevation in serum
creatine phophokinase is recognised.40 41
Rarely, this is asso-
ciated with myoglobinuria and renal failure.42 43
Myositis is
more commonly described in children than adults.
3.3.4 Central nervous system
Central nervous system (CNS) involvement in adults is
uncommon. Most reports originate from Japan and occur in
children.44 45
The main clinical syndrome is an encephalitis or
encephalopathy manifesting in the form of decreased con-
sciousness and seizures about three days (range 0–7 days)
following the onset of upper respiratory tract symptoms. Focal
neurological signs such as paresis, aphasia, choreoathetosis and
cranial nerve palsies are less common. Cerebrospinal fluid
(CSF) examination may be normal or reveal an elevation in
protein or white cell count. Imaging by CT or MRI may be
normal and if so, is indicative of a good prognosis and full
recovery may be anticipated.46
Young age and abnormal CT/MRI
findings are associated with a poor outcome including death or
recovery with severe neurological sequelae (a fuller description
is given in Section 4.2.6).
Acute necrotising encephalopathy is a rare fulminant
syndrome associated with multifocal brain lesions that is
described mainly in Japan.46
Other rare manifestations include
transverse myelitis and Guillain-Barre´ syndrome.47 48
Reye’s syndrome, characterised by an encephalopathy, acute
fatty liver, association with aspirin use and high mortality
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(,40%), is a special situation that is almost exclusively seen in
children and adolescents.46
Nevertheless, physicians managing
adults are advised to be aware of this complication (a fuller
description is given in Section 4.2.6.1.1).
3.3.5 Others
Other complications rarely encountered in adults with influ-
enza A infection include toxic shock syndrome in conjunction
with secondary S aureus infection49 50
and parotitis.51
Otitis
media is more commonly encountered in children than adults.
3.4 Avian influenza A (H5N1) infection in humans
Human infections have been caused by different avian
influenza A viruses in the past, including H9N2, H7N7, H7N3
and H7N2. In recent years, outbreaks of human infections by a
novel strain of avian influenza A (H5N1) have raised particular
concerns globally regarding the risk of a human pandemic.52
These concerns have been due in part to recognition that (a)
avian influenza A (H5 N1) can pass directly from birds to
humans and that (b) once in humans, avian influenza A
(H5N1) causes severe disease with a high mortality.
The full spectrum of human illness associated with avian
influenza A (H5N1) infection is not completely known.
Descriptions of the clinical features of influenza A (H5N1)
infection in humans are based largely on case series of
hospitalised patients. Subclinical infections, mild illnesses and
atypical presentations of influenza A (H5N1) infections in
humans have been reported, but the frequency of such
infections is difficult to determine.53–55
In hospitalised patients, an ILI similar to that associated with
seasonal influenza A (H1N1 or H3N2) infection is recognised.
Gastrointestinal symptoms are present in a relatively large
proportion of both adult and paediatric cases, in contrast to the
relatively low incidence of gastrointestinal symptoms in
seasonal influenza. The majority of patients develop a severe
primary viral pneumonia usually associated with lymphopenia,
thrombocytopenia and deranged liver function tests. Renal
failure and multi-organ failure may develop subsequently.
Mortality is high. A more detailed description is given in
Appendix 10.
Should influenza A (H5N1) acquire efficient human-to-
human transmission capabilities, it may result in an influenza
pandemic. In such an event, the clinical features of human
H5N1 disease may alter.
4 CLINICAL FEATURES IN CHILDREN
Summary
1. The commonest presenting features of influenza during an
epidemic are fever, cough and rhinorrhoea. In infants,
fever with non-specific symptoms or diarrhoea and
vomiting is common; in older children pharyngitis and
headache are frequent.
2. The clinical features of influenza in children during a
pandemic cannot be forecast.
3. Children with underlying respiratory or cardiac disease,
immune compromise or who are non-ambulant are more
likely to be severely affected.
4. The younger the child the more likely hospital admission
will be needed.
5. The severe and life-threatening complications of influenza
are likely to be
– bacterial pneumonia
– acute respiratory distress syndrome
– encephalopathy or encephalitis presenting as seizures
or altered mental status.
4.1 What are the clinical features of uncomplicated
influenza in children?
The clinical features of influenza presenting in a pandemic
cannot be predicted as they appear to be dependent on the
strain of influenza and, in some respects, the host. A new strain
of influenza A responsible for an epidemic or pandemic may
result in a different spectrum of clinical features than previous
strains.56 57
Common features during previous epidemics have been
described and depend on the age of the child. The studies of
clinical features are hospital based and are therefore likely to
reflect more severe illness. These are nevertheless informative
as one of the main issues in a pandemic is which patients
require hospital admission. In young children presenting to
primary care in a non-pandemic influenza season there are no
specific clinical features that distinguish influenza from other
winter viruses.58
Previously healthy infants and children
4.1.1 Neonates may present with non-specific signs of sepsis
such as pallor, floppiness, (poor peripheral circulation, poor
tone), lethargy, poor feeding, episodes of apnoea.59
Fever may
be the only presenting feature. A North American study
identified influenza as the most common reason for children
aged 0–60 days being admitted to hospital during an epidemic
with fever as the only clinical feature.60
4.1.2 Infants and very young children (under two years).
Fever may be the only presenting feature in this age group too.
They may also be irritable and toxic and are more likely than
older children to present with gastrointestinal symptoms such
as diarrhoea and vomiting. Febrile convulsions, particularly
repeated convulsions, are positively associated with influenza
A.61
Otitis media is also a common complication in children.62
Admission rates for under 2 year olds are 12 times higher than
children aged 5–17 years.63
4.1.3 Older children. The presentation does not differ
significantly from adults. Common features are sudden onset
of high fever, chills (76–100%), cough, headache, sore throat,
fatigue (51–75%), nasal stuffiness and conjunctivitis (26–
50%). Fever tends to settle 2–4 days later though a dry cough
and clear nasal discharge last for 1–2 weeks.59
A clinical
prediction model from North America for influenza in
children has shown that the triad of cough, headache and
pharyngitis had a sensitivity of 80% and a specificity of 78%
for a positive viral culture for influenza.64
The subjects, mean
age 6 years, presented during an epidemic to a suburban
emergency department with a febrile respiratory illness and
one or more symptoms of influenza. A Finnish retrospective
study of children referred to hospital from 1980–99 with
influenza confirmed by antigen testing reported that the
median age for those with influenza A was 2 years. The most
common features were cough, fever and rhinorrhoea.62
These
were also the commonest features reported in a Chinese
study where the mean age of the subjects with influenza A
was 4 years.65
Children with underlying medical conditions
4.1.4 Children with asthma and other chronic medical
conditions66
(table 4.1) and those who are not ambulant67
experience substantial morbidity during influenza seasons with
a disproportionate number requiring inpatient care and
ventilatory support. Of the 22% of previously healthy children
who were hospitalised with influenza in Texas during the
winter of 1998–99, 75% were under 1 year old. Of the 60%
hospitalised who had underlying conditions, only 27% were
under 1 year.68
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4.2 Complications and rarer clinical features (table 4.2)
4.2.1 Pneumonia
As in adults, influenza can present with either primary viral
pneumonia or bacterial pneumonia most commonly caused by S
pneumoniae or S aureus. There is much less published about
pneumonia complicating influenza in children.
An outbreak of severe pneumococcal pneumonia in children
occurred in Iowa in the winter of 1995–96. This was coincident
with an epidemic of influenza (H1N1). Compared with
controls, patients were 12 times more likely to have experienced
a recent ILI. There were also more likely to have family
members with the illness and to have positive serology in the
convalescent period. Many of these patients required chest
drainage.69
Another study in 2002 of 202 children with proven influenza
reported that 78 who had chest radiographs had either
radiographic evidence of viral pneumonia or normal radio-
graphs. No child had lobar pneumonia reported.70
Evidence from recent outbreaks of avian influenza (H5N1) in
Hong Kong and Vietnam suggests that while some children had
mild disease,71
others appeared to have multi-organ disease
including acute respiratory distress syndrome (ARDS).57
All
children who developed progressive pneumonia with ARDS
died. There were no reports of bacterial pneumonia.
There is no reason to believe that, apart from ARDS,
pneumonia complicating influenza presents differently from
CAP in children.72
The general clinical indicators for severity assessment of
lower respiratory tract infection are summarised in the British
Thoracic Society guidelines72
(Appendix 8). Failure to improve
following 48 hours of antibiotics, or deterioration including a
new, distinct spike of fever, should also be treated as severe and
further complicating factors sought.
4.2.2 Croup
The clinical course of croup caused by influenza appears to be
more severe than croup caused by the more common parain-
fluenza virus.73
It is more likely to be complicated by bacterial
tracheitis.62
4.2.3 Otitis media
Influenza is a well recognised cause of otitis media.74
It is the
commonest bacterial superinfection of influenza and is
reported in approximately 25% patients aged ,5 years.75
4.2.4 Bronchiolitis
Influenza ranks second only to respiratory syncytial virus as a
cause of bronchiolitis.76
The clinical features are the same.77
4.2.5 Febrile convulsions
Children with influenza may present with febrile convulsions.
In a community study in the Netherlands, recurrent febrile
seizures were positively related to influenza A. It was
recommended that children who have had a previous febrile
convulsion should be immunised against influenza A.61
4.2.6 Encephalopathy and encephalitis
These complications are described in small case series.
4.2.6.1 Encephalopathy
This is defined as depressed or altered level of consciousness
including lethargy and/or extreme irritability in younger
children or significant change in personality or behaviour
persisting beyond 24 hours, or confusion (older children).
Encephalopathy usually presents as seizures within several
days of the onset of fever.78
Seizures at this point are usually the
first symptom of involvement of the CNS. Febrile convulsions,
which are more likely to be repeated with influenza than with
other causes of fever, generally occur with the onset of fever.
Disturbances of behaviour and neurological deficit have been
reported. A rapid and severe clinical course is usual with
encephalopathy and is thought to be due to brain oedema
mediated by cytokines rather than by direct invasion of the
brain. Steroids are therefore considered. 202 children with
encephalopathy were recognised in Japan between 1997 and
2001. Death occurred in 31%, residual neurological deficit in
26% and full recovery in 43%.79
4.2.6.1.1 Reye’s syndrome
This is a rare childhood acute encephalopathy associated with
liver dysfunction. The cause is unknown but it typically follows
Table 4.2 Complications of influenza in children
Complication Incidence Comments
Respiratory
Otitis media Very common
Lung Common (,10%) The younger, the more likely to
require hospital admissionBronchiolitis
Primary viral pneumonia
Secondary bacterial pneumonia
Croup Presenting feature in
,5%
Worse clinically than with para-
influenza
Central nervous system
Febrile convulsions Common May be repeated
Encephalopathy Rare Includes acute necrotising
encephalopathy, Reye’s syndrome
Encephalitis Rare
Guillain-Barre´ Rare
Others
Myositis Rare
Myocarditis Rare
Pericarditis Rare
Table 4.1 The most common underlying conditions in
children admitted to hospital, Texas 1998–99.68
Asthma (42%)
Congenital anomalies mostly cardiac (28.5%)
Chronic lung disease of prematurity
Immunodeficiencies
Malignancies
Renal disease
Haemaglobinopathies
Diabetes (and other metabolic conditions)
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viral illness and there is a clear association with aspirin therapy:
thus an innate susceptibility coupled with aspirin taken for
relief of viral symptoms. Influenza (particularly influenza B) is
commonly implicated.80
There was a dramatic fall in incidence
following warnings about aspirin use in children.81
It is possible
that children on long term aspirin treatment for medical
conditions may be at increased risk if they develop influenza
infection.
Reye’s syndrome is characterised by protracted vomiting and
encephalopathy in afebrile patients with minimal or absent
jaundice, and hepatomegaly in 50% of patients. It comprises:
N acute non-inflammatory encephalopathy with an altered
level of consciousness
N elevation of ammonia levels 24–48 hours after the onset of
mental status changes (the most frequent laboratory
abnormality)
N hepatic dysfunction with a liver biopsy showing fatty
metamorphosis or a more than threefold increase in alanine
aminotransferase (ALT), aspartate aminotransferase (AST).
Neurological symptoms usually occur 24–48 hours after the
onset of vomiting. Lethargy is usually the first neurological
manifestation. Diarrhoea and hyperventilation may be the first
signs in children younger than two years.
Other investigations. Head CT scanning may reveal
cerebral oedema but results are usually normal. An electro-
encephalogram (EEG) may reveal slow wave activity in the
early stages and flattened waves in advanced stages.
Cerebrospinal fluid may or may not have increased opening
pressure with white blood cells (WBCs) fewer than 9/ml3
(usually lymphocytes).
There is no specific treatment for Reye’s syndrome. Key
aspects of management are correction of metabolic imbalance
and reduction of intracranial pressure. Advice should be
requested from a specialist in metabolic medicine. Many
children have an underlying inborn error of metabolism.
Mortality has fallen from 50% to less than 20% as a result of
earlier diagnosis and more aggressive therapy.
4.2.6.1.2 Acute necrotising encephalopathy
Acute necrotising encephalopathy occurs mainly in Japan
where it was first described in 1995. An estimated 100 deaths
per annum are related to CNS complications of influenza in
Japan.82
This suggests either a genetic predisposition for this
complication or a variation in the strains of influenza
circulating in Japan. Acute necrotising encephalopathy is
characterised by high fever, convulsions and coma in children
aged 1–5 years. The onset is 2–4 days after the respiratory
symptoms and fewer than 10% of patients survive.83
There are
no specific markers although some patients have raised liver
transaminases. In many, the CSF is normal. Symmetrical
multifocal brain lesions are seen and bilateral thalamic
involvement is characteristic and may be demonstrated on
MRI.83
4.2.6.2 Encephalitis
This is defined as encephalopathy plus two of the following:
fever of 38˚C or higher, seizures, focal neurological findings,
WBC .5 cells/ml in CSF, electroencephalogram findings
consistent with encephalitis, abnormal neuro-imaging.84
4.2.6.3 Differential diagnoses
These must be considered when a child presents with altered
level of consciousness or irritability. There is good evidence of
an increased risk of meningococcal disease following influenza
infection.85
During a pandemic, the focus will be on diagnosing
influenza-related illness. Other neurological conditions or drug
toxicity, for example, may be missed.
4.2.7 Myositis
A literature review of 316 cases of myositis86
suggested that this
was a complication mainly of schoolchildren. The calf muscles
are predominantly affected. Rhabdomyolysis and renal failure
are rare.
4.2.8 Myocarditis and pericarditis
These are also rare complications but have been described in
children with underlying medical conditions.62
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PART 1
Clinical management in primary care
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Thorax 2007;62(Suppl I):i14–i18. doi: 10.1136/thx.2006.073080
5 GENERAL MANAGEMENT AND INVESTIGATIONS IN
PRIMARY CARE
5.1 Triage
With widespread concern during a pandemic, a significantly
increased demand for advice and consultation should be
anticipated. There are likely to be significantly higher consulta-
tion rates for all types of respiratory tract infections including
those which are normally managed well at home using over the
counter remedies (for example, febrile colds, sore throat with
temperatures). Consequently, demand management in both the
practice and the Primary Care Trust (PCT) will be crucial to
avoid the service’s capacity to triage care being overwhelmed.
Guidance on demand management and health service
delivery is given in the Primary Care Operational Plan (see
Section 1.4).87
Management decisions of patients with influenza should be
based primarily on:
N an assessment of illness severity
N identification of whether the individual is in an ‘‘at risk’’
group
N current advice from Department of Health/local public health
officials based on the epidemiology of the pandemic.
Patients who are not considered to be at high risk and who
have no features suggesting severe disease or complications
may not need to be seen in face-to-face consultations by a
primary care clinician.
5.2 General advice and symptomatic treatment in adults
All patients presenting in general practice with symptoms
suggestive of influenza (except perhaps those in whom urgent
admission is required) should be given both general advice and
advice on symptomatic treatment. It is important that clinicians
identify and address individual concerns and expectations,
provide information about the illness, and provide information
about what patients can do to help themselves and when they
should seek further help. Some useful facts that can be
provided to the patient are included in Box 5.1.
There is little scientific evidence for most symptomatic and
self-help treatment, but experience suggests that some of the
following may help, and are unlikely to cause harm:
N treatment of fever, myalgias and headache with paracetamol
or ibuprofen
N rest
N drinking plenty of fluids
N avoiding smoking
N consider: short course of topical decongestants, throat
lozenges, saline nose drops.
5.3 General management in children
Many infants and children will have coughs and mild fevers
which may be due to other infections such as respiratory
syncytial virus, especially over the winter months. These
children should be managed in the usual way at home by
parents with antipyretics and fluids.
Note: aspirin should not be used in children.
5.3.1 Children with high fever (.38.5˚C) and cough
or influenza-like symptoms
Management of these children is determined by disease severity
(see Appendix 5). The principles of symptomatic management
are similar to those for adults.
Recommendations
N Children under one year of age year and those at high risk of
complications (see Appendix 2) should be seen and assessed
by a general practioner (GP) or at the A&E department.
N Children age over 1 but under 7 years of age may be seen by
a nurse or a GP and those aged 7 years and above may be
seen by a member of the community health team (for
example, community pharmacist).
N All children (and parents) should be given advice on
antipyretics and fluids.
N Aspirin is contraindicated in children (aged under 16 years).
5.4 When should patients re-consult?
Examples of what should prompt a patient to re-consult are
given in Box 5.2. Patients who are started on antiviral agents
(see Section 7 for indications for antiviral use) would be
expected to begin to improve within 48 hours of starting
treatment. Failure to improve two days after starting an
Abbreviations: BTS, British Thoracic Society; CAP, community acquired
pneumonia; COPD, chronic obstructive pulmonary disease; CRP,
C-reactive protein; GP, general practitioner; HDU, high dependency unit;
HPA, Health Protection Agency; ICU, intensive care unit; ILI, influenza-like
illness; PCR, polymerase chain reaction; PCT, Primary Care Trust
Box 5.1 Information about influenza to provide to
patients
N Influenza is caused by a number different types of
‘‘influenza’’ viruses.
N The incubation period is typically 1–4 days and infected
adults are usually contagious from the day of illness onset
to five days after. Children are typically contagious for
seven days, although sometimes for longer.
N Fever usually declines after 2–3 days and normally
disappears by the sixth day.
N Cough, weakness and fatigue can persist for 1–2 weeks
and up to six weeks.
N Antibiotics do not benefit most people with influenza but are
sometimes needed to treat secondary infections.
Important note: this information may be modified once a
pandemic occurs.
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antiviral agent is an indication to re-consult. At the time of re-
consultation, an alternative diagnosis should be considered as
well as the occurrence of any influenza-related complications.
Recommendations
N Any rapid deterioration following first consultation should
prompt a patient to re-consult.
N Failure to improve two days after starting an antiviral agent
is an indication to re-consult.
N If the first consultation did not involve contact with a
physician, re-consultation should preferably involve a
physician, usually a GP.
5.5 What general investigations should be done in the
community?
Recommendation
N General investigations, including a chest x ray, are not
necessary for the majority of patients managed in the
community.
5.6 What microbiological investigations should be
undertaken for patients in the community?
The aim of microbiological investigations early in a pandemic
(UK alert levels 1, 2 and 3) will be to confirm that influenza A is
circulating in the local community. Once a pandemic is
established (UK alert level 4), microbiological investigations
are not recommended routinely or likely to be available readily.
Routine testing for bacterial pathogens is not recommended at
any stage.
Recommendations
N Where possible, early in a pandemic (UK alert levels 1, 2 and
3), nose and throat swabs, or nasopharyngeal swabs (in
children), in virus transport medium should be submitted to
the local laboratory.
N Once a pandemic is established (UK alert level 4), micro-
biological investigations are not recommended.
6 CRITERIA FOR HOSPITAL REFERRAL
6.1 Which adults require hospital referral?
Adults with uncomplicated influenza infection usually do not
require hospital referral. Patients who might require hospital
admission fall into two main groups; those with worsening of a
pre-existing medical condition and those with an influenza-
related complication.
6.1.1 Worsening of pre-existing medical condition
Patients who experience a worsening or clinical deterioration of
pre-existing medical problems due to influenza infection
should be managed according to recommended best practice
for the medical condition in question. For instance, a patient
with an acute exacerbation of chronic obstructive pulmonary
disease (COPD) triggered by influenza infection should be
managed according to current NICE Guidelines for COPD.88
Those with worsening of a pre-existing condition are likely to
be in a group at ‘‘high risk’’ of influenza-related respiratory
complications and consequently at risk of hospitalisation or
death (Appendix 2). This group should be promptly reassessed
if the illness is getting worse and considered for hospital
referral.
6.1.2 Influenza-related pneumonia
Pneumonia is the commonest influenza-related complication
requiring hospital admission. Patients complaining of new or
worsening dyspnoea should be carefully assessed for signs of
pneumonia. If pneumonia is diagnosed, disease severity
assessment is recommended and hospital referral made
accordingly.
There is no validated severity assessment tool developed
specifically for influenza-related pneumonia. The CRB-65 score
(table 6.1) is a well validated severity assessment tool
developed for patients with community acquired pneumonia
(CAP)89 90
and recommended in the British Thoracic Society
(BTS) CAP Guidelines 2004 for use in the community setting.72
It is offered as an example of an assessment tool for influenza-
related pneumonia.
The use of any severity assessment tool does not replace
clinical judgement. A patient’s social circumstances should also
always be taken into account.
In view of the rapid and fulminant course of primary viral
pneumonia, patients with pneumonia who have bilateral chest
signs (crackles) should be considered for hospital referral.
6.1.3 Other complications
Other influenza-related complications are uncommon. There
are no specific recommendations relating to criteria for hospital
admission or disease severity assessment in these cases.
Recommendations
N Patients with clinically defined uncomplicated influenza
infection would be expected to make a full recovery. They
Box 5.2 Examples of what should prompt patients
to re-consult
N Shortness of breath at rest or while doing very little
N Painful or difficult breathing
N Coughing up bloody sputum
N Drowsiness, disorientation or confusion
N Fever for 4–5 days and not starting to get better (or
getting worse)
N Started to feel better then developing high fever and
feeling unwell again
N If taking antiviral drugs (for example, oseltamivir),
symptoms should start to improve within two days. Lack
of any improvement after two days from starting antiviral
drugs is an indication to re-consult.
Important note: this information may be modified once a
pandemic occurs.
Table 6.1 Severity assessment used to determine the
management of influenza-related pneumonia in patients in
the community (CRB-65 score)
CRB-65 score* Recommended action
0 Likely suitable for home treatment
1 or 2 Consider hospital referral,
particularly with score 2
3 or 4 Urgent hospital referral
Any (0 to 4), in the presence of
bilateral chest signs of pneumonia
Consider hospital referral
Score 1 point for each feature present: Confusion (Mental Test Score of (8,
or new disorientation in person, place or time); Respiratory rate >30/min;
Blood pressure (SBP ,90 mmHg or DBP (60 mmHg); age >65 years.
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require good symptomatic management, access to antiviral
treatment, information about the natural history, and advice
as to when to re-consult.
N Patients with new or worsening symptoms—particularly
shortness or breath or recrudescent fever not responding to
treatment—should be examined to assess the presence and
severity of influenza-related pneumonia.
N Patients with worsening of pre-existing comorbid medical
conditions should be managed according to best practice for
that condition with reference to published disease-specific
guidelines, if available.
N In patients with influenza-related pneumonia clinically,
hospital referral and assessment should be considered for
patients with a CRB-65 score of 1 or 2 (particularly score 2)
and urgent admission for those with CRB-65 score of 3 or
more.
N Patients with bilateral chest signs of pneumonia should be
referred to hospital for further assessment regardless of
CRB-65 score.
N The CRB-65 score does not replace clinical judgment.
6.2 Which children require hospital referral? (see
Appendix 5)
Recommendation
N Children who are severely ill should be referred for
assessment for admission. Indicators of severe disease are:
(1) cyanosis
(2) severe dehydration
(3) altered conscious level
(4) complicated or prolonged seizures
(5) signs of sepsis such as extreme pallor, hypotension, a
floppy infant
(6) signs of respiratory distress such as markedly
raised respiratory rate, grunting, intercostal recession
or breathlessness with chest signs (a useful severity
assessment tool for respiratory distress taken
from the BTS pneumonia guidelines is given in
Appendix 8).
7 ANTIVIRAL USE IN PRIMARY CARE
7.1 Introduction
The guidance given in this Section summarises the key
recommendations relevant to primary care. Full details
relating to the principles and practice of antiviral use in
adults and children are provided in Sections 13 and 19
respectively. Guidance relating to the delivery of antivirals is
laid out in detail in the UK Operational Framework for
stockpiling, distributing and using of antiviral drugs in the
event of pandemic influenza5
and in the Primary Care
Operational Plan.
7.2 What drugs should be used for antiviral treatment
during a pandemic?
Recommendations (see Appendix 9)
N The antiviral treatment of choice is oseltamivir (TamifluH).
This is given as a five-day course of oral tablets; 75 mg twice
daily for adults. Liquid suspension is available for children
from the age of 1 year upwards (see table 7.1).
7.3 What are the anticipated benefits of antiviral
treatment?
From clinical trial data accrued to date and based on seasonal,
interpandemic influenza, the anticipated positive effect of
antivirals in a pandemic will be:
(a) reduction of illness duration by 24 hours, and therefore
more rapid mobilisation of affected individuals including
essential workers
(b) a possible reduction in hospitalisation of infected indivi-
duals
(c) a reduction of subsequent antibiotic use by infected
individuals.
The evidence accrued to date does not suggest there will be a
reduction of overall mortality, nor does it rule it out.
7.4 Who should receive antiviral drugs?
Recommendations
N Ideally, antiviral treatment should be offered to every patient
who is over one year of age who
(a) has an acute influenza-like illness
(b) fever (>38˚C in adults, or >38.5˚C in children) and
(c) presents within 48 hours of the onset of symptoms.
N Exceptions:
(i) Patients who are unable to mount an adequate febrile
response—for example, the immunocompromised or
very elderly—may still be eligible for antiviral treat-
ment despite the lack of documented fever.
(ii) Immunosuppressed patients, including those on long
term corticosteroid therapy, may suffer more prolonged
viraemia, and could possibly benefit from antiviral
therapy commenced later than 48 hours after the onset
of influenza-like illness (ILI).
(iii) Patients who are severely ill, but who have not been
hospitalised due to non-clinical reasons, may benefit
from antiviral therapy commenced later than 48 hours
after the onset of ILI. There is no strong evidence to
support antiviral use in these exceptional situations.
7.5 What are the adverse effects of oseltamivir?
The commonest adverse effect of oseltamivir is nausea in about
10% of patients. This can be managed with mild anti-emetic
medication. Other side effects are listed in Appendix 9.
7.6 Delivery of antivirals in primary care
National distribution arrangements are laid out in the UK
Operational Framework for stockpiling, distributing and using
antiviral drugs in the event of pandemic influenza5
and the
Primary Care Operational Plan. The drug will be made available
through these arrangements to pharmacies, PCTs and/or GP
surgeries.
Table 7.1 Adult and child dosages of oseltamivir
Child aged .1 year;
body weight 15 kg or lower
30 mg 12-hourly
Child .15–23 kg 45 mg 12-hourly
Adult, and child >24 kg 75 mg 12-hourly
Dose to be reduced by 50% if creatinine clearance is less than 30 ml/
minute.
i16 Provisional guidelines from the BIS/BTS/HPA with the Department of Health
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